JPH0222327A - Polymer consisting citric acid and diamine, and its production and use - Google Patents
Polymer consisting citric acid and diamine, and its production and useInfo
- Publication number
- JPH0222327A JPH0222327A JP1054831A JP5483189A JPH0222327A JP H0222327 A JPH0222327 A JP H0222327A JP 1054831 A JP1054831 A JP 1054831A JP 5483189 A JP5483189 A JP 5483189A JP H0222327 A JPH0222327 A JP H0222327A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- citric acid
- polyamides
- diamine
- polymer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 title claims abstract description 83
- 150000004985 diamines Chemical class 0.000 title claims abstract description 25
- 238000004519 manufacturing process Methods 0.000 title claims description 8
- 229920000642 polymer Polymers 0.000 title abstract description 60
- 239000004952 Polyamide Substances 0.000 claims abstract description 21
- 229920002647 polyamide Polymers 0.000 claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 11
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 10
- 125000001931 aliphatic group Chemical group 0.000 claims abstract description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 6
- 125000006239 protecting group Chemical group 0.000 claims abstract description 6
- 125000003118 aryl group Chemical group 0.000 claims abstract description 5
- 239000012736 aqueous medium Substances 0.000 claims abstract description 4
- 229910052760 oxygen Inorganic materials 0.000 claims abstract 2
- 238000000034 method Methods 0.000 claims description 22
- 238000006068 polycondensation reaction Methods 0.000 claims description 16
- 239000000126 substance Substances 0.000 claims description 11
- -1 benzyl ester Chemical class 0.000 claims description 8
- 230000002378 acidificating effect Effects 0.000 claims description 7
- 238000009833 condensation Methods 0.000 claims description 6
- 230000005494 condensation Effects 0.000 claims description 6
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 5
- 238000013270 controlled release Methods 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000000853 adhesive Substances 0.000 claims description 2
- 230000001070 adhesive effect Effects 0.000 claims description 2
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 239000002253 acid Substances 0.000 abstract description 14
- 229910052717 sulfur Inorganic materials 0.000 abstract description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 238000005984 hydrogenation reaction Methods 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 43
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 29
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 24
- 239000000203 mixture Substances 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- 229920001577 copolymer Polymers 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 239000004472 Lysine Substances 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 125000002843 carboxylic acid group Chemical group 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 238000012696 Interfacial polycondensation Methods 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 125000005462 imide group Chemical group 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- 235000019766 L-Lysine Nutrition 0.000 description 5
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 5
- XXAYGJGDVLSEML-LBPRGKRZSA-N benzyl (2s)-2,6-diaminohexanoate Chemical compound NCCCC[C@H](N)C(=O)OCC1=CC=CC=C1 XXAYGJGDVLSEML-LBPRGKRZSA-N 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 125000004185 ester group Chemical group 0.000 description 5
- 238000006116 polymerization reaction Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 238000007327 hydrogenolysis reaction Methods 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 238000002329 infrared spectrum Methods 0.000 description 4
- 235000018977 lysine Nutrition 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine Chemical compound [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 229920002988 biodegradable polymer Polymers 0.000 description 3
- 239000004621 biodegradable polymer Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000006482 condensation reaction Methods 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- OOTFVKOQINZBBF-UHFFFAOYSA-N cystamine Chemical compound CCSSCCN OOTFVKOQINZBBF-UHFFFAOYSA-N 0.000 description 3
- 229940099500 cystamine Drugs 0.000 description 3
- 229960003067 cystine Drugs 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 125000004427 diamine group Chemical group 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 2
- 239000004158 L-cystine Substances 0.000 description 2
- 235000019393 L-cystine Nutrition 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000005227 gel permeation chromatography Methods 0.000 description 2
- NAQMVNRVTILPCV-UHFFFAOYSA-N hexane-1,6-diamine Chemical compound NCCCCCCN NAQMVNRVTILPCV-UHFFFAOYSA-N 0.000 description 2
- 150000003949 imides Chemical group 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 229920002521 macromolecule Polymers 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 230000037353 metabolic pathway Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 235000011837 pasties Nutrition 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- 239000012465 retentate Substances 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
- HFFLGKNGCAIQMO-UHFFFAOYSA-N trichloroacetaldehyde Chemical compound ClC(Cl)(Cl)C=O HFFLGKNGCAIQMO-UHFFFAOYSA-N 0.000 description 2
- HVLLSGMXQDNUAL-UHFFFAOYSA-N triphenyl phosphite Chemical compound C=1C=CC=CC=1OP(OC=1C=CC=CC=1)OC1=CC=CC=C1 HVLLSGMXQDNUAL-UHFFFAOYSA-N 0.000 description 2
- GMKMEZVLHJARHF-UHFFFAOYSA-N (2R,6R)-form-2.6-Diaminoheptanedioic acid Natural products OC(=O)C(N)CCCC(N)C(O)=O GMKMEZVLHJARHF-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- NULDEVQACXJZLL-UHFFFAOYSA-N 2-(2-aminoethyldisulfanyl)ethylazanium;chloride Chemical compound Cl.NCCSSCCN NULDEVQACXJZLL-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical group CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000012695 Interfacial polymerization Methods 0.000 description 1
- GQWNECFJGBQMBO-UHFFFAOYSA-N Molindone hydrochloride Chemical compound Cl.O=C1C=2C(CC)=C(C)NC=2CCC1CN1CCOCC1 GQWNECFJGBQMBO-UHFFFAOYSA-N 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001371 alpha-amino acids Chemical class 0.000 description 1
- 235000008206 alpha-amino acids Nutrition 0.000 description 1
- 150000004984 aromatic diamines Chemical class 0.000 description 1
- 239000003637 basic solution Substances 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 238000006065 biodegradation reaction Methods 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000001734 carboxylic acid salts Chemical class 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
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- 229910052801 chlorine Inorganic materials 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000007791 dehumidification Methods 0.000 description 1
- 125000001142 dicarboxylic acid group Chemical group 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
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- 239000012153 distilled water Substances 0.000 description 1
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- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 230000009791 fibrotic reaction Effects 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
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- 238000002513 implantation Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
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- 238000010255 intramuscular injection Methods 0.000 description 1
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- GMKMEZVLHJARHF-SYDPRGILSA-N meso-2,6-diaminopimelic acid Chemical compound [O-]C(=O)[C@@H]([NH3+])CCC[C@@H]([NH3+])C([O-])=O GMKMEZVLHJARHF-SYDPRGILSA-N 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
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- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
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- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000011970 polystyrene sulfonate Substances 0.000 description 1
- 229960002796 polystyrene sulfonate Drugs 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000002787 reinforcement Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 231100000161 signs of toxicity Toxicity 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000003894 surgical glue Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 229940029273 trichloroacetaldehyde Drugs 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
- C08G69/02—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids
- C08G69/26—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids derived from polyamines and polycarboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
- A61K9/2045—Polyamides; Polyaminoacids, e.g. polylysine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L17/00—Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
- A61L17/06—At least partially resorbable materials
- A61L17/10—At least partially resorbable materials containing macromolecular materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
- A61L26/0019—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Materials Engineering (AREA)
- Surgery (AREA)
- Vascular Medicine (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Transplantation (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Heart & Thoracic Surgery (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Polyamides (AREA)
- Medicinal Preparation (AREA)
- Materials For Medical Uses (AREA)
Abstract
Description
【発明の詳細な説明】
[産業上の利用分野]
この発明は、クエン酸の1位および3位の炭素原子(即
ち水酸基に対しβ位)へ結合したカルボキシル基を介す
るジアミンとクエン酸の縮合によって得られたポリアミ
ド類からなる親水性重合体およびその製造方法、および
有機体内で薬物の制御持続放出をさせることが可能な担
体または貯蔵体として、または縫合糸または結紮糸とし
て、または筋肉組織、靭帯および損傷した骨の代替およ
び強化のための外科的補綴として、また外科用接着剤と
してこれらの生物分解性ポリマーを適用することに関す
るものである。Detailed Description of the Invention [Industrial Application Field] This invention relates to the condensation of diamine and citric acid via carboxyl groups bonded to the 1st and 3rd carbon atoms of citric acid (i.e., β-position relative to the hydroxyl group). hydrophilic polymers consisting of polyamides obtained by and methods for their production, and as carriers or depots capable of providing controlled and sustained release of drugs in organisms, or as sutures or ligatures, or in muscle tissues, It concerns the application of these biodegradable polymers as surgical prostheses for the replacement and reinforcement of ligaments and damaged bones and as surgical adhesives.
[従来の技術]
親水性官能基を有するポリアミド類は既に報告されてい
る。ミノウラら[ジャーナル・オブ・ポリマー・サイエ
ンス(J 、 Polym、 Sc、)、A−1部、5
巻、2441頁(1967年)]およびN。[Prior Art] Polyamides having hydrophilic functional groups have already been reported. Minoura et al. [Journal of Polymer Science (J, Polym, Sc,), Part A-1, 5
Vol. 2441 (1967)] and N.
オガタら[ジャーナル・オブ・ポリマー・サイエンス、
13巻、1793頁(1975年)]によって報告され
た、ヘキサメヂレンジアミンとL−酒石酸の縮合により
製造されたポリアミド類を挙げることができるが、ここ
で前者は水溶性であるが低分子量であり、後者は水に不
溶である。またL−リシンおよび脂肪族または芳香族ノ
カルボン酸から誘導された水溶性ポリアミドは、マクロ
モレキュラーレ・ヒエミー(MakroIIol、 C
heffi、)、109巻、239頁(1967年)お
よびジャーナル・オブ・ポリマー・サイエンス、A−I
L 96.2413頁(1971年)に報告されている
界面重縮合、あるいはマクロモレキュラーレ・ヒエミー
186巻、939頁(1985年)に報告されている溶
液重縮合によって製造された。Ogata et al. [Journal of Polymer Science,
13, p. 1793 (1975)], the former is water-soluble but has a low molecular weight. and the latter is insoluble in water. Water-soluble polyamides derived from L-lysine and aliphatic or aromatic nocarboxylic acids are also available from Macromolecules Chemia (MakroIIol, C
Heffi, ), vol. 109, p. 239 (1967) and Journal of Polymer Science, A-I.
It was produced by interfacial polycondensation as reported in L 96, p. 2413 (1971), or solution polycondensation as reported in Macromolecules Chemie, Vol. 186, p. 939 (1985).
クエン酸から誘導されたポリアミド類はこれまで報告さ
れていない。しかしカルボン酸基3個および水酸基1個
を有するこのポリマーが存在すると、少なくとも2個の
親水性官能基を有する重合体を製造することが可能であ
り、そのような親水性官能基によって、媒質のいかなる
p Hおよび極性溶媒中でも確実な水溶性を付与するこ
とができろ。一方、不安定な分子内結合で、遊離した、
もしくは封鎖されたカルボキシル基が存在すると重合体
は種々の分子を結合するのに使用し得る高い反応性が付
与される。固有の溶解度を低下させ機械的な低抗性を増
大させることが望ましく考えられる場合は、例えば薬物
を直鎖式重合体の骨格とイオン結合または共有結合によ
って結合し、または重合体を橋かけ結合するのに使用で
きる。Polyamides derived from citric acid have not been reported to date. However, the presence of this polymer with 3 carboxylic acid groups and 1 hydroxyl group makes it possible to prepare polymers with at least two hydrophilic functional groups, which allow the medium to It should be possible to provide reliable water solubility at any pH and in polar solvents. On the other hand, due to unstable intramolecular bonds, free
Alternatively, the presence of blocked carboxyl groups imparts to the polymer high reactivity that can be used to bond various molecules. If it is considered desirable to reduce intrinsic solubility and increase mechanical resistance, for example, the drug can be attached to the backbone of a linear polymer by ionic or covalent bonds, or the polymer can be cross-linked. It can be used to
[発明の態様コ
この発明のポリマーは、特に下記の構造式(式中、nは
1000より低い整数で、好ましくは20〜300の間
にあり、Zは炭素原子2〜10個、好ましくは2〜8個
を有する直鎖式または分枝鎖式脂肪族鎖から選ばれ、O
HlSITおよびC001〜■のような親水基を含み、
あるいは中間に酸素原子または硫黄原子を挿入してもよ
く、またはZは一〇 6 H,−のようなアリール鎖、
または−Cit−c、t−t、−co、−または−CI
−[、−C,tl。[Aspects of the Invention] The polymers of this invention are particularly characterized by the following structural formula: where n is an integer lower than 1000, preferably between 20 and 300, and Z has 2 to 10 carbon atoms, preferably 2 selected from linear or branched aliphatic chains having ~8 O
Contains hydrophilic groups such as HlSIT and C001~■,
Alternatively, an oxygen atom or a sulfur atom may be inserted in the middle, or Z is an aryl chain such as 10 6 H,-,
or -Cit-c, t-t, -co, -or -CI
-[, -C, tl.
のようなアルキルアリール鎖から選ばれ、〜はZが非対
称である場合、結合の2つの型を表す)で表される。selected from alkylaryl chains such as and represented by ~ represents two types of bonding if Z is asymmetric).
事実この場合、このポリマーは、成長しつつあるポリマ
ーの遊離カルボキシル基とジアミンの1またはそれ以外
のアミノ基との縮合から生成した2つの型の単位から構
成される。In fact, in this case the polymer is composed of two types of units resulting from the condensation of free carboxyl groups of the growing polymer with one or other amino groups of the diamine.
治療に有用であるために、ことに薬物の制御放出形格で
は、このポリマーは好ましくは生物分解性であり、分解
の際に生成される分子が有機体にとって無毒で、しかも
容易に排出されるものでなければならない。ナイロン(
ny ton ;商標)のような脂肪族直鎖式ポリアミ
ドは生体内加水分解に対して比較的鋭敏でないことが知
られており、これに反して、この発明のポリシトラミド
類は親水性であり、水溶性であるから、蛋白質分解酵素
が存在しなくても生体内でなんら支障なく加水分解され
、タレブス回路の代謝生産物であるクエン酸を遊離し、
有毒な生産物の蓄積または生成の危険なしに自然な代謝
経路によって分解され、排出される。ジアミン単量体が
生きている哺乳動物の有機体内に自然に存在する分子で
ある場合、すべての生物分解の生産物は自然の代謝経路
によって有機体から排除され、したがってその重合体は
生物溶解性であると言い得る。In order to be useful in therapy, particularly in controlled release forms of drugs, the polymer is preferably biodegradable, such that the molecules produced upon degradation are non-toxic to organisms and are easily excreted. It has to be something. Nylon(
In contrast to aliphatic linear polyamides such as nyton®, which are known to be relatively insensitive to in vivo hydrolysis, the polycitramides of the present invention are hydrophilic and water soluble. Because it is a bioactive substance, it can be hydrolyzed in the body without any problems even in the absence of proteolytic enzymes, liberating citric acid, which is a metabolic product of the Taleb's cycle.
It is broken down and excreted by natural metabolic pathways without the risk of accumulation or formation of toxic products. If the diamine monomer is a naturally occurring molecule in a living mammalian organism, all products of biodegradation will be eliminated from the organism by natural metabolic pathways and the polymer will therefore be biosoluble. It can be said that
この発明のポリマー製造に含まれるジアミン類は好まし
くは対称性のエチレンジアミン、ヘキサメチレンジアミ
ン、3.6−シオキサー1.8−オクチルジアミン、シ
スタミンまたはフェニレンジアミンのような単純な脂肪
族または芳香族ジアミン類である。The diamines involved in the preparation of the polymers of this invention are preferably simple aliphatic or aromatic diamines such as symmetrical ethylenediamine, hexamethylenediamine, 3,6-thioxal-1,8-octyldiamine, cystamine or phenylenediamine. It is.
またこれらのジアミン類は、ジアミノピメリン酸のよう
にその他の遊離浅水基、例えばヒドロキシル基またはカ
ルボキシル基のような基を含んでいてもよく、その場合
、重縮合中に反応する可能性のある基は重合前に保護し
ておかなければならない。These diamines may also contain other free shallow water groups, such as hydroxyl or carboxyl groups, as in diaminopimelic acid, in which case the groups that may react during polycondensation are Must be protected before polymerization.
特にこの発明のポリマーを医薬用として適用しようとす
る場合は、シスタミン、L−オルニチン、L−シスチン
、ことにL−リシンのような、天然に有機体に存在して
いるジアミン類が好ましい。Particularly when the polymers of the invention are to be applied for pharmaceutical purposes, diamines which occur naturally in organisms are preferred, such as cystamine, L-ornithine, L-cystine and especially L-lysine.
またこれらアミン類の右旋性立体異性体またはそのラセ
ミa合物も使用できる。Furthermore, dextrorotatory stereoisomers of these amines or their racemic a compounds can also be used.
また少なくとも2種類の異なったジアミン類とクエン酸
との重縮合によって得られたコポリマーもこの発明に包
含される。Also included in the present invention are copolymers obtained by polycondensation of at least two different diamines and citric acid.
この発明の好ましい対象は、L−リシンとクエン酸の縮
合によって得られる重合体であるが、その場合、し−リ
シンのカルボン酸が重合に対し好適に保護され、またク
エン酸はその中心炭素原子に結合しているヒドロキシル
残基およびカルボン酸残基が縮合による重合に対し好適
に保護されていることが好ましい。A preferred subject of the invention is a polymer obtained by condensation of L-lysine and citric acid, in which case the carboxylic acid of lysine is suitably protected against polymerization, and the citric acid is It is preferred that the hydroxyl and carboxylic acid residues bonded to are suitably protected against polymerization by condensation.
このようにして得られたポリマーは、その保護基を除去
すると親水性であり、その分子量に応じて水および極性
非プロトン性有機溶媒およびヒドロキシル化された溶媒
のような水と相溶性の溶媒にさまざまな程度で溶解し得
る。それらのアルコールに対する溶解度は医薬品形態の
製造に特に有用であり、現在、生物分解性ポリマーとし
てその利用が積極的な興味の対象となっているα−アミ
ノ酸の縮合によって得られるポリマーの大半が医薬品産
業で使用されることが稀な溶媒にしか通常溶解しないこ
とは注目すべきである。The polymer thus obtained is hydrophilic upon removal of its protecting groups and, depending on its molecular weight, is compatible with water and water-compatible solvents such as polar aprotic organic solvents and hydroxylated solvents. May be soluble to varying degrees. Their solubility in alcohol makes them particularly useful for the production of pharmaceutical forms, and currently the majority of polymers obtained by condensation of α-amino acids are of active interest in the pharmaceutical industry, their use as biodegradable polymers. It is noteworthy that it is usually soluble only in solvents that are rarely used in
この発明の好ましいポリマーは有毒でなく、酵素が関与
しまたは関与しない生体内加水分解によって分解され、
天然に有機体に存在する無毒物質、即ちクエン酸および
し一リジンを放出する。Preferred polymers of this invention are non-toxic and are degraded by enzymatic or non-enzymatic hydrolysis in vivo;
Releases non-toxic substances naturally occurring in organisms, namely citric acid and lysine.
この発明のもう一つの対象はこれらのポリシトラミド類
の製造方法である。この方法は基本的にクエン酸の2位
の炭素原子と結合しているOH基およびCOOH基を封
鎖したクエン酸とジアミンを重縮合し、保護基を除去す
ることによって実施することからなる。Another subject of the invention is a process for the production of these polycitramides. This method basically consists of polycondensing citric acid in which the OH group and COOH group bonded to the 2-position carbon atom of citric acid are blocked, and a diamine, and removing the protecting group.
2位の炭素原子に結合するOH基およびC0OH基の封
鎖は、クエン酸の他のC00H基が遊離したまま残るよ
うに選択的でなければならない。The capping of the OH and C0OH groups attached to the carbon atom in position 2 must be selective so that the other C00H groups of citric acid remain free.
また封鎖した基は重縮合反応条件で高度の安定性を保有
しなければならないが、重縮合の終了後、ポリアミド骨
格の分解を招くことなく除去することが可能でなければ
ならない。The capped groups must also have a high degree of stability under the polycondensation reaction conditions, but must be able to be removed after the polycondensation is complete without causing decomposition of the polyamide backbone.
下記の反応式:
%式%
によってクエン酸とアルデヒドを反応させることにより
、構造式(d)を有する1、3−ジオキソラン−4−オ
ン型誘導体を製造することによってOH基およびC0O
H基を同時に保護するのが好ましい。By reacting citric acid with an aldehyde according to the following reaction formula: % OH group and COO
Preferably, the H groups are protected at the same time.
ホルムアルデヒド(R=H)、脂肪族アルデヒド(R=
C,−C,アルキル)、トリクロロアセトアルデヒド(
R= CCIs)およびベンズアルデヒド(R=CsH
s)とクエン酸との縮合反応生成物は既知化合物であり
、それらは酸性または塩基性いずれかの媒質中で加水分
解されて前駆物質クエン酸を再生することが知られてい
る。Formaldehyde (R=H), aliphatic aldehyde (R=
C, -C, alkyl), trichloroacetaldehyde (
R=CCIs) and benzaldehyde (R=CsH
The condensation reaction products of s) with citric acid are known compounds, which are known to be hydrolyzed in either acidic or basic media to regenerate the precursor citric acid.
また今回、式(d)で示されるジオキソランの接触水素
化によってもクエン酸基を再生し得ることが判明し、こ
れによって、ジアミン単位が封鎖を必要とした反応性官
能基を有する場合、クエン酸およびジアミン単位の封鎖
を同時にとり除くことが可能となった。It has now also been found that the citric acid group can be regenerated by catalytic hydrogenation of dioxolane of formula (d), which shows that when the diamine unit has a reactive functional group that required capping, the citric acid group It became possible to simultaneously remove the blockade of diamine units and diamine units.
重合体生成へ誘導する縮合反応を実施するためには、酸
および/またはアミン基を活性化することが必要である
。ジカルボン酸およびジアミンの有機溶液にジシクロへ
キシルカルボッイミドまたはN、N’−カルボニル−ジ
イミダゾールのようなカップリング試薬を導入すること
も可能であるが、既知方法によって酸塩化物形態とする
酸の予備活性化の方が好ましい。その目的のため、封鎖
したクエン酸を溶媒の存在または存在なしで過剰の塩化
チオニルと反応される。またトリメチルシリル基との置
換またはその他の任意の標準的な試薬によるアミン基の
予備活性化も可能である。またペプチド合成に使用され
るようなその他のカップリング試薬も重縮合反応に都合
よく使用できる。In order to carry out the condensation reaction leading to polymer formation, it is necessary to activate the acid and/or amine groups. Although it is also possible to introduce a coupling reagent such as dicyclohexylcarboimide or N,N'-carbonyl-diimidazole into an organic solution of dicarboxylic acid and diamine, it is also possible to introduce the acid into the acid chloride form by known methods. Pre-activation of is preferred. For that purpose, the blocked citric acid is reacted with excess thionyl chloride in the presence or absence of a solvent. Also possible is substitution with a trimethylsilyl group or preactivation of the amine group by any other standard reagent. Other coupling reagents, such as those used in peptide synthesis, can also be conveniently used in polycondensation reactions.
重合は、溶液中で行う既知方法または界面重縮合によっ
て実施できるが、界面重縮合は酸塩化物のような極めて
反応性に富んだ物質の場合に、好ましくは環境温度に近
い温度またはそれ以下の温度で適用し得る。Polymerization can be carried out by known methods in solution or by interfacial polycondensation, which in the case of highly reactive substances such as acid chlorides is preferably carried out at temperatures close to or below ambient temperature. Can be applied at temperatures.
当技術の熟柿者であれば、ポリアミド製造に適した既知
方法を参考とし、クエン酸基を保護するジオキソラン基
の塩基性水性媒質における不安定性を考慮することによ
って特殊な分子m特徴を有するポリマーの製造に最適な
重合条件を選ぶことが可能であろう。ジアミンとジカル
ボン酸塩化物の重縮合は発生する塩酸を除去する易溶性
塩基の存在で既知方法により実施される。溶液重合の場
合は、通常トリエチルアミンまたはピリジンのような第
3級アミンを添加するが、界面重合の場合はアルカリ金
属の水溶性炭酸塩を使用する。Those skilled in the art will be able to create polymers with special molecular characteristics by referring to known methods suitable for polyamide production and by taking into account the instability of the dioxolane group that protects the citric acid group in basic aqueous media. It would be possible to choose the optimal polymerization conditions for production. Polycondensation of diamines and dicarboxylic acid chlorides is carried out by known methods in the presence of a readily soluble base which removes the hydrochloric acid generated. In the case of solution polymerization, a tertiary amine such as triethylamine or pyridine is usually added, while in the case of interfacial polymerization a water-soluble carbonate of an alkali metal is used.
重縮合の前に保護した封鎖基をとり除く方法は選んだ保
護方法によって異なる。式(d)のジオキソランの形で
クエン酸を封鎖したのなら、ポリアミド骨格の分解をき
たすことなく酸または塩基の水性媒質または水性アルコ
ール媒質中で環境温度でOH基およびC00H基を再生
することができる。The method for removing the protected blocking group prior to polycondensation will depend on the protection method chosen. If the citric acid is sequestered in the form of dioxolane of formula (d), it is possible to regenerate the OH and C00H groups in an acidic or basic aqueous or hydroalcoholic medium at ambient temperature without decomposition of the polyamide backbone. can.
ジアミンが、縮合反応に関わる2個のNH,基以外に反
応性基を有する場合、この発明の方法は、重縮合の前に
、さらにこれらの基を保護する追加的な段階およびポリ
マー中に存在するこれらの封鎖基をとり除く段階を含む
。これらのポリマー中のクエン酸単位の0 )1および
COO)Iの封鎖をとり除くための方法によって同時に
実施し得る。ポリマー骨格の分解をきたすことなく封鎖
基を切断するのが明らかに必要であり、例えばジアミン
のヒドロキシル基をエステルまたはカルボナートの形で
、またカルボン酸基をベンジルエステルの形で封鎖でき
る。ベンジルエステル封鎖基は接触水素化により、また
は緩和な条件下で加水分解することによってカルボン酸
を再生させ得るので好ましく、これに反して、直鎖式脂
肪族アルコールのエステルでは、ポリアミド鎖が少なく
とも部分的に分解される強酸または強塩基媒質中でのみ
加水分解される。If the diamine has reactive groups other than the two NH, groups involved in the condensation reaction, the process of the present invention requires additional steps to protect these groups and the presence in the polymer before polycondensation. removing these blocking groups. It can be carried out simultaneously by methods for removing the 0 ) 1 and COO) I blockade of the citric acid units in these polymers. There is clearly a need to cleave off the capping groups without causing decomposition of the polymer backbone; for example, the hydroxyl groups of diamines can be capped in the form of esters or carbonates, and the carboxylic acid groups in the form of benzyl esters. Benzyl ester capping groups are preferred because they allow regeneration of the carboxylic acid by catalytic hydrogenation or by hydrolysis under mild conditions, whereas in esters of linear aliphatic alcohols the polyamide chain is at least partially Hydrolyzed only in strong acidic or strong basic media.
式(d)のジオキソランの形で保護したクエン酸二塩化
物とジアミンとの界面重縮合Iこよって得られる生成物
は、期待した単位、即ち、リシンをジアミンの例として
挙げると、その酸基がベンジルエステルで保護された形
の下式(Ila)および(nb)
で表され、またこの非対称ジアミンの結合について考え
られる2つの型に対応する、下式で要約された形で表さ
れ得る単位だけで構成されているのではなく、低重縮合
のような、ジオキソラン基の分子内副反応によって生じ
た下記の要約された式(III)
(式中、aおよびbは整数、〜はアミン萌駆物質の非対
称性に起因ずろ種々の結合の可能性を表す)に対応する
環式イミド基を有している単位を含んでいろ。Interfacial polycondensation of citric acid dichloride protected in the form of dioxolane of formula (d) with a diamine I. The product thus obtained contains the expected units, i.e., taking lysine as an example of a diamine, its acid group is represented by the formulas (Ila) and (nb) in benzyl ester-protected form and can be represented in the summarized form by the following formulas, corresponding to the two possible types of bonding of this asymmetric diamine: The following condensed formula (III) (wherein a and b are integers, ~ is an amine Due to the asymmetry of the parent material, it contains units with cyclic imide groups corresponding to various bonding possibilities.
イミド基を有する単位の割合は、ジオキソランのR置換
基の性質お上び重縮合の条件、ことに溶媒によって変わ
る。The proportion of units having imide groups depends on the nature of the R substituents of the dioxolane and on the polycondensation conditions, especially the solvent.
式(III)で示されるコポリマーはこの発明の対象物
である。これらは生物分解性ポリマーとして、あるいは
式(■)および(V)で示されるポリマー合成の中間体
として使用できる。Copolymers of the formula (III) are the subject matter of this invention. These can be used as biodegradable polymers or as intermediates in the synthesis of polymers of formulas (■) and (V).
式(III)のポリマーを接触水素化すると、そのベン
ノルエステルからカルボン酸基、およびジオキソラン環
に含まれているヒドロキシル基およびカルボキシル基が
遊離され、要約された式(IV)一コ
デ
Q=0
(式中、aおよびbは整数である)
で示されるポリマーが得られる。Catalytic hydrogenation of the polymer of formula (III) liberates the carboxylic acid group from its bennorester, as well as the hydroxyl and carboxyl groups contained in the dioxolane ring, giving the formula (IV) one code Q=0 ( A polymer of the formula (where a and b are integers) is obtained.
ポリマー(IV)を得るエステル基の水素化分解は時に
完全達成が難しいことがあり、必要であれば、ジメチル
ホルムアミドおよび水の混合液の塩酸溶液のような酸溶
液を用いる反応によって水素化分解後ら残留しているエ
ステル基を加水分解してもよい。Hydrogenolysis of the ester groups to obtain polymer (IV) is sometimes difficult to achieve completely and, if necessary, after hydrogenolysis by reaction with an acid solution such as a hydrochloric acid solution of a mixture of dimethylformamide and water. The remaining ester groups may be hydrolyzed.
この発明のもう一つの対象は、式(■)で示されるコポ
リマーおよびリジン以外のジアミン類から製造された式
(■a)
1ビ
で示される類似のポリマーからなる〇
ポリマーの環式イミド基は、水性媒質中、塩基との反応
により!またはそれ以上の窒素−カルボニル結合の開裂
によって開環し、これを酸性にすると、式(V)
Ap−Bq (V)
(ここで、Aは)
H
Bは
Zは前記と同意義、pおよびqは整数でp十q=a+b
。Another object of the present invention is that the cyclic imide group of the copolymer of formula (■) and a similar polymer of formula (■a) 1bi produced from diamines other than lysine is , in an aqueous medium, by reaction with a base! Or, when the ring is opened by cleavage of more nitrogen-carbonyl bonds and made acidic, the formula (V) Ap-Bq (V) (where A is) H B is Z is as defined above, p and q is an integer p1q=a+b
.
p>aであり、〜は前記と同意義である)で示される不
規則に分布した2つの異なった型の非環式単位を含んだ
直鎖式コポリマーを生じる。A linear copolymer containing two different types of randomly distributed acyclic units is obtained, with p>a and ~ as defined above.
式(V)の化合物はこの発明のもう一つの対象物である
。Compounds of formula (V) are another subject of this invention.
この発明のポリマーが対称的なジアミンから製造された
場合は、起部−起部結合および起部−尾部結合によって
生じる異性体はもはや存在しないから、式(I)(ここ
で〜は−である)で示される一層規則的な構造の生成物
が得られる。If the polymers of this invention are prepared from symmetrical diamines, the isomers resulting from the origin-to-origin and origin-to-tail bonds no longer exist, so that formula (I) (where ~ is - ) is obtained with a more regular structure.
最後にこの発明のもう一つの対象は、生物分解性(ある
時は生物溶解性)である式(r)、(III)、(■)
および(V)のポリシトラミド類およびそれらの製薬上
許容し得る塩基との塩を薬物の制御放出型または持続放
出型医薬品形態の貯蔵器または担体として使用し、ある
いは外科の縫合糸または結紮糸、または外科的補綴とし
て、または接着剤として使用する用途である。Finally, another object of the present invention is that formulas (r), (III), (■) which are biodegradable (sometimes biosoluble)
and (V) polycitramides and their salts with pharmaceutically acceptable bases as reservoirs or carriers for controlled-release or sustained-release pharmaceutical forms of drugs, or surgical sutures or ligatures, or Applications include use as a surgical prosthesis or as an adhesive.
共有結合またはイオン結合によって有効成分をこの発明
のポリマー結合させて高分子プロドラッグを作成でき、
あるいは既知方法によりポリマーとよく混和し、または
ビーズ状、ホイル状、棒状または細孔性要素形となし得
るボ、リマーへ吸収させてもよく、または高分子マイク
ロエマルションのようなポリマー集合系へ加えてもよい
。またポリマーでコーティングし、既知の技術を用いて
特にカプセルまたはマイクロカプセルの形に調製するこ
とらできる。Active ingredients can be linked to the polymers of this invention by covalent or ionic bonds to create macromolecular prodrugs;
Alternatively, it may be adsorbed by known methods into bodies, reamers, which are miscible with polymers or may be in the form of beads, foils, rods or porous elements, or added to polymer assembly systems such as polymeric microemulsions. You can. They can also be coated with polymers and prepared using known techniques, especially in the form of capsules or microcapsules.
疾病を治癒しまたは予防するよう設計された薬物または
ある種の生物学的機能を調節する薬物は、この発明のポ
リマーで既知の方法により製剤化することができる。Drugs designed to cure or prevent disease or modulate certain biological functions can be formulated with the polymers of this invention by known methods.
これらの医薬形態は、経口または経鼻腔、静脈または筋
肉内注射、または皮下埋込みのいずれかの薬物投与様式
に適合させることができろ。These pharmaceutical forms may be adapted for modes of drug administration, either oral or nasal, intravenous or intramuscular injection, or subcutaneous implantation.
この発明のポリマーは、マウス腹腔内または筋肉内(7
00+*g/ kg)、ラット静脈内(250+ag/
kg)注射によって、死亡または何らか明白な毒性徴候
を起こさないので、無毒である。The polymer of this invention can be administered intraperitoneally or intramuscularly (7
00+*g/kg), rat intravenous (250+ag/kg), rat intravenous (250+ag/kg),
kg) injection does not cause death or any obvious signs of toxicity and is therefore non-toxic.
またラット脇腹へ皮下包埋すると、ときに極めて弱い繊
維反応が起こることがあるが、生成物の局所耐容性は優
れている。The local tolerability of the product is excellent, although subcutaneous embedding in the rat flank can sometimes cause very weak fibrotic reactions.
以下にこの発明の実施例を報告する。Examples of this invention are reported below.
実施例1
シトロベンザルジクロリドおよびL−リシンベンノルエ
ステルの界面重縮合
(a) L−リシンベンジルエステルのジーp−)ルエ
ンスルホン酸塩
L−リシン30g(20,5,IO”モル)および蒸留
したベンジルアルコール70m1(67,6,10−雪
モル)をディーン・スターク式抽出装置へ加える。これ
にp−トルエンスルホン酸・l水和物88.5g(46
,5,10−”モル)およびベンゼン3QQalを追加
する。反応中に生成する水が全部除去されるまで混合物
を還流下に加熱する。溶液をビーカーへ移しメタノール
100m1を加える。室温でエチルエーテル500II
+1を加えることによって塩が沈澱する。加温しながら
沈澱をメタノール300II11に採取し、エチルエー
テルで再沈澱させる。L−リシンベンジルエステルのN
、N’−ジトシレート100gを得る。収率84%。M
、P、163℃。Example 1 Interfacial polycondensation of citrobenzal dichloride and L-lysine benyl ester (a) J-p-)luenesulfonate of L-lysine benzyl ester 30 g (20,5, IO" moles) of L-lysine and distilled Add 70 ml (67,6,10-snow moles) of benzyl alcohol to the Dean-Stark extractor. To this is added 88.5 g (46
, 5,10-" mol) and benzene 3QQal. Heat the mixture under reflux until all the water formed during the reaction is removed. Transfer the solution to a beaker and add 100 ml of methanol. Ethyl ether 500 II at room temperature.
Salt is precipitated by adding +1. The precipitate was collected in methanol 300II11 while heating and reprecipitated with ethyl ether. N of L-lysine benzyl ester
, 100 g of N'-ditosylate are obtained. Yield 84%. M
, P, 163°C.
(b)シトロベンザル[式(d) : RはCs I−
1sの化合物コクエン酸78g(0,41モル)および
ベンズアルデヒド90gを撹拌機を付けた三頚フラスコ
へ加える。混合物を約50℃に加熱し、温度を75〜8
0℃に保つようにPfO842,5gを少量ずつ添加す
る無水リン酸は赤く変色し、ついで混合物と接触すると
黒く変色する。添加の終末時には混合物は黒色となる。(b) Citrobenzal [Formula (d): R is Cs I-
78 g (0.41 mol) of the 1s compound cocitric acid and 90 g of benzaldehyde are added to a three-necked flask equipped with a stirrer. Heat the mixture to about 50°C and reduce the temperature to 75-8
Phosphoric anhydride, to which 2.5 g of PfO is added little by little while maintaining the temperature at 0° C., turns red and then turns black when it comes into contact with the mixture. At the end of the addition the mixture turns black.
さらに約80℃で90分間撹拌を続ける。反応終末点で
、砕氷片を加えた乳鉢べ黒色の油状物質を熱特注入する
。油状物質は氷と接触すると固化する。4NKOHを加
えてpH8としながら混合物を粉砕する。過剰のベンズ
アルデヒドを酢酸エチルで抽出する。黒色の水溶液を0
℃に冷却し、5rictで酸性とする。シトロベンザル
は油状物質の形でフラスコ底部に分離する。Stirring is continued for an additional 90 minutes at about 80°C. At the end of the reaction, hot inject a black oily substance into a mortar with crushed ice chips added. Oily substances solidify on contact with ice. The mixture is triturated while adding 4NKOH to pH 8. Excess benzaldehyde is extracted with ethyl acetate. 0 black aqueous solution
Cool to 0.degree. C. and acidify with 5 rict. The citrobenzal separates in the form of an oil at the bottom of the flask.
エチルエーテルでこれを抽出する。エーテル溶液をpi
−1が中性となるまで水洗し、無水M g S O4で
乾燥し蒸発する。白色の固体的70gを得る。これを加
温しながら酢酸エチル300Illに溶解する。Extract this with ethyl ether. Pi ether solution
-1 is washed with water until it becomes neutral, dried with anhydrous MgSO4, and evaporated. 70 g of a white solid are obtained. This was dissolved in 300 Ill of ethyl acetate while heating.
tIZ色の溶液を冷却した後、石油エーテル15011
1を追加すると無色の結晶としてシトロベンザルが沈澱
する。結晶51.5gを回収する。収率45%。After cooling the tIZ colored solution, petroleum ether 15011
When 1 is added, citrobenzal precipitates as colorless crystals. 51.5 g of crystals are collected. Yield 45%.
M、P、185℃(C)E s COOCt Hs /
石油エーテル)。IRおよびNMRスペクトルで同定す
る。M, P, 185℃ (C) E s COOCt Hs /
petroleum ether). Identification by IR and NMR spectra.
(C)シトロベンザルジクロリド
(b)によって得たジカルボン酸14gおよび5OC1
* 40m1(予じめトリフェニルホスフィツトから蒸
留)を冷却器および塩化カルシウム除湿管を付けたフラ
スコ中で加熱する。反応混合物を撹拌しながらジカルボ
ン酸が完全に溶解するまで加熱還流する(約2時間)。(C) 14 g of dicarboxylic acid obtained with citrobenzal dichloride (b) and 5OC1
* 40 ml (previously distilled from triphenylphosphite) are heated in a flask fitted with a condenser and a calcium chloride dehumidification tube. The reaction mixture is heated to reflux with stirring until the dicarboxylic acid is completely dissolved (approximately 2 hours).
さらに15分間還流を続ける。反応終末時、過剰の塩化
チオニルを減圧下に留去する。残留物にベンゼンまたは
トルエン30m1を加え、混合物をr遇する。P液を植
物炭の存在で加熱し、r過し、蒸発乾固する。Continue refluxing for an additional 15 minutes. At the end of the reaction, excess thionyl chloride is distilled off under reduced pressure. 30 ml of benzene or toluene are added to the residue and the mixture is stirred. The P solution is heated in the presence of vegetable charcoal, filtered and evaporated to dryness.
残留物をベンゼン20m1に溶解し、石油エーテルで再
沈澱させる。シトロベンザルジクロリド9゜4%を無色
針状結晶として得る。収率的60%0M、P、82℃(
トルエン/n−ヘキサン)。The residue is dissolved in 20 ml of benzene and reprecipitated with petroleum ether. 9.4% of citrobenzal dichloride is obtained as colorless needle-shaped crystals. Yield 60% 0M, P, 82°C (
toluene/n-hexane).
この化合物は水で容易に加水分解され、自然に環式無水
物に変化する。したがって氷晶は使用前に調製すべきで
ある。This compound is easily hydrolyzed in water and spontaneously transforms into a cyclic anhydride. Ice crystals should therefore be prepared before use.
(d)重縮合
実験室用混合装置中で、L−リシンベンジルエステルの
N、N’−シト・シレードア、6g(13,02゜1O
−3モル)、炭酸ナトリウム・lO水和物7.45g(
26,04,ICl3モル、遊離酸基の中和に必要)お
よびドデシル硫酸ナトリウム0.5g[メルク(Mer
k)社製](ジカルボン酸塩化物の10重量%)を水−
ベンゼン混合液(60cm’、V/V、66/33)に
激しく撹拌しながら溶解する。(d) In a polycondensation laboratory mixing apparatus, 6 g (13,02° 1O
-3 mol), 7.45 g of sodium carbonate 1O hydrate (
26,04, 3 moles of ICl, required for neutralization of free acid groups) and 0.5 g of sodium dodecyl sulfate [Merck
k)] (10% by weight of dicarboxylic acid chloride) in water-
Dissolve in benzene mixture (60 cm', V/V, 66/33) with vigorous stirring.
激しく撹拌しながら(1分間12000〜15000回
転)、ベンゼン40m1に溶解したシトロベンザルジク
ロリド4.54g(14,32,IO−’モル)および
水201に溶解した炭酸ナトリウム8.2g(28,6
4,IO−”モル)を、6分間以内にそれぞれの溶液が
90容量%添加されるよう同時に添加する。1〜2分間
撹拌を続け、ついで残りの溶液(10%)を1分間以内
に追加してさらに2分間撹拌を続ける。環境温度から反
応終末時には最終45〜50℃となるまで温度を上昇さ
せる。With vigorous stirring (12,000-15,000 revolutions per minute), 4.54 g (14,32, IO-' mol) of citrobenzal dichloride dissolved in 40 ml of benzene and 8.2 g (28,6 mol) of sodium carbonate dissolved in 201 ml of water
4, IO-" moles) are added simultaneously such that 90% by volume of each solution is added within 6 minutes. Stirring is continued for 1-2 minutes, then the remaining solution (10%) is added within 1 minute. Continue stirring for an additional 2 minutes.The temperature is increased from ambient temperature to a final temperature of 45-50°C at the end of the reaction.
添加から1分後にポリマーが混合物から沈澱する。The polymer precipitates from the mixture 1 minute after addition.
反応の中間点で反応混合物は黄色く変色する。反応終末
時、希塩酸を加えて混合物を酸性としp t−t2に近
付ける。pi−1が中性となるまで重合体を水洗し、減
圧下に約50℃の温度で乾燥し、秤量する。式(III
)のポリマー5.1gを回収する(収率83%)。(R
=c、n、)。At the halfway point of the reaction, the reaction mixture turns yellow. At the end of the reaction, dilute hydrochloric acid is added to acidify the mixture to approach pt-t2. The polymer is washed with water until pi-1 is neutral, dried under reduced pressure at a temperature of about 50°C, and weighed. Formula (III
) was recovered (yield 83%). (R
=c, n,).
このポリマーは黄色の固体で、アセトン、CHCl+、
ctitcttのようなkIA素化溶媒、ジオキサンお
よびテトラヒドロフランに溶解する。ベンゼン、トルエ
ン、メタノール、エタノール、水には不溶である。This polymer is a yellow solid that can be mixed with acetone, CHCl+,
Dissolve in kIA chlorination solvents such as ctitctt, dioxane and tetrahydrofuran. Insoluble in benzene, toluene, methanol, ethanol, and water.
平均分子量は24000(ジオキサン溶液:ポリスチレ
ン標準品を使用したゲル浸透クロマトグラフィーで測定
)。Average molecular weight is 24,000 (measured by gel permeation chromatography using dioxane solution: polystyrene standard).
実施例2
ノトロクロラールジクロリドおよびL−リシンベンジル
エステルの界面重縮合
(+1)ントロクロラール[式(d:RはCC1,)の
化合物]
撹拌装置、冷却器、滴下ロートを付けた三頚フラスコに
、窒素大気下、クエン酸77g(0,4モル)および無
水クロラール99.3g(0,67モル)を加える。装
置を水浴で0℃に冷却する。氷を加えることによって温
度を0〜5℃に保ち、撹拌しながら約90分間で濃硫酸
12(1mlを加えろ。ざらに0℃で2時間撹拌を続け
、ついで反応混合物を環境温度に上げて約10時間撹拌
する。反応終末時、混合物は白色ペースト状の外観を呈
し、これを砕氷片を加えたビーカーへ移す。酢酸エチル
およびエチルエーテルで白色の固体を抽出する。Example 2 Interfacial polycondensation of notrochloral dichloride and L-lysine benzyl ester (+1) torochloral [compound of formula (d: R is CC1,)] In a three-necked flask equipped with a stirrer, a condenser, and a dropping funnel, Under a nitrogen atmosphere, 77 g (0.4 mol) of citric acid and 99.3 g (0.67 mol) of chloral anhydride are added. Cool the apparatus to 0°C in a water bath. Maintain the temperature at 0-5°C by adding ice and add 1 ml of concentrated sulfuric acid 12 (1 ml) over approximately 90 minutes while stirring. Stirring is continued for approximately 2 hours at 0°C, then the reaction mixture is brought to ambient temperature. Stir for about 10 hours. At the end of the reaction, the mixture has a white pasty appearance and is transferred to a beaker with crushed ice chips. Extract the white solid with ethyl acetate and ethyl ether.
p tlが中性となるまで有機層を水洗し、無水硫酸ナ
トリウムで乾燥し、蒸発乾固してピンク色をした粘稠な
油状物質を得る。この油状物質を加温しながらクロロホ
ルム300m1に溶解する。冷却するとシトロクロラー
ルは無色粉末状の形で沈澱する。この沈澱を沸騰酢酸エ
チル350m1に溶解する。環境温度まで冷却した黄色
の溶液に石油エーテルを徐々に加えることにより白色の
結晶沈澱を生じる。シトロクロラール96.5gを回収
する。The organic layer is washed with water until p tl is neutral, dried over anhydrous sodium sulfate, and evaporated to dryness to give a pink viscous oil. This oil is dissolved in 300 ml of chloroform with heating. On cooling, citrochloral precipitates in the form of a colorless powder. This precipitate is dissolved in 350 ml of boiling ethyl acetate. Gradual addition of petroleum ether to the yellow solution cooled to ambient temperature produces a white crystalline precipitate. 96.5 g of citrochloral are recovered.
収率75%。M、P、163℃(CH,C00C,H。Yield 75%. M, P, 163°C (CH, C00C, H.
/石油エーテル)。/petroleum ether).
(b)シトロクロラールジクロリド
氷晶は実施例1−cで報告した方法により製造する。た
だしベンゼンの代わりに、蒸発して得られた残留物を!
、2−ジクロロエタン20m1に溶解する。(b) Citrochloral dichloride ice crystals are prepared by the method reported in Example 1-c. But instead of benzene, use the residue obtained by evaporation!
, dissolved in 20 ml of 2-dichloroethane.
ジカルボン酸14gからジクロリド9.5gを白色針状
結晶の形で得ろ。M、P、79〜80℃(CC1,/石
油エーテル)。From 14 g of dicarboxylic acid, 9.5 g of dichloride are obtained in the form of white needle-like crystals. M, P, 79-80°C (CC1,/petroleum ether).
(c) L−リシンベンジルエステルとの界面重縮へ
L−リシンベンジルエステルのN、No−シトシレー)
8.9g(15,2,10−’モル)、炭酸ナトリウム
・IO水和物8.71g(30,4,I O−3モル)
およびドデシル硫酸ナトリウム0.7gを激しく撹拌し
ながら水20cm3、ジクロロメタンIOc+*3.1
.2−ジクロロエタン10cm’および水30gを含ん
だ混合液に溶解ずろ。(c) Interfacial polycondensation of L-lysine benzyl ester with L-lysine benzyl ester (N, No-cytosylate)
8.9 g (15,2,10-' mol), sodium carbonate IO hydrate 8.71 g (30,4, IO-3 mol)
and 0.7 g of sodium dodecyl sulfate with vigorous stirring, water 20 cm3, dichloromethane IOc+*3.1
.. Dissolve in a mixture containing 10 cm' of 2-dichloroethane and 30 g of water.
塩素溶媒から選ばれた混合液500m1(V/V:50
/ 50 )に溶解したシトロクロラールジクロリド
6g(+ 6.7.10−’モル)および水20c+e
’に溶解した炭酸ナトリウム9.58g(33,4,1
03モル)を同時に加える。方法は先に記載した方法と
同様である。500ml of mixed liquid selected from chlorine solvents (V/V: 50
/50) 6 g (+6.7.10-' mol) of citrochloral dichloride and 20 c+e of water
9.58 g of sodium carbonate (33,4,1
03 mol) is added at the same time. The method is similar to that described above.
反応終末時、粗製重合体を含有する有機層を採取ずろ。At the end of the reaction, collect the organic layer containing the crude polymer.
水石を酸性とし、ジクロロメタン50m1で抽出する(
2回)。有機溶液を集めて水洗し、硫酸マグネシウムで
乾燥する。有機溶媒を蒸発して重合体を回収し、真空下
に50℃で乾燥する。式(III:lはCC1,)の粗
製ポリマー7gを回収ずろ(収率87%)。Make water stone acidic and extract with 50 ml of dichloromethane (
twice). The organic solution is collected, washed with water, and dried over magnesium sulfate. The polymer is recovered by evaporating the organic solvent and dried at 50° C. under vacuum. 7 g of crude polymer of formula (III: 1 = CC1) was recovered (87% yield).
式(III:RはCG +3)の粗製ポリマーは実施例
1で得られたポリマーと同様の溶解度を示す。平均分子
mは20000である。The crude polymer of formula (III: R = CG +3) shows a similar solubility to the polymer obtained in Example 1. The average molecule m is 20,000.
ポリマーの分子量は、最終温度および使用した溶媒など
重縮合の条件によって変わる。ベンゼン/水混合液(5
0150、v/v)の場合、重縮合によって分子fi2
0000のポリマーを生成するが、ベンゼン/水/水混
合液(50/20/30)では分子量はtooooに過
ぎず、ジクロロメタン/ジクロロエタン/水/水の混合
液(25/25/20/30)では14000である。The molecular weight of the polymer will vary depending on the polycondensation conditions, such as the final temperature and the solvent used. Benzene/water mixture (5
0150, v/v), the molecule fi2 is formed by polycondensation
0000 polymer is produced, but the molecular weight is only toooo in the benzene/water/water mixture (50/20/30), and in the dichloromethane/dichloroethane/water/water mixture (25/25/20/30). It is 14,000.
実施例3
式(IV)のポリマーの製造
ジメチルホルムアミド(DMF)100cm3に溶解し
た実施例1または2で得られた粗製共重合体5gにパラ
ジウム化炭素(10%パラジウム−活性炭)Igを添加
する。混合物がそれ以上水素を吸収しなくなるまで24
時間60℃に保つ。Example 3 Preparation of a polymer of formula (IV) To 5 g of the crude copolymer obtained in Example 1 or 2 dissolved in 100 cm@3 of dimethylformamide (DMF), Ig of palladized carbon (10% palladium on activated carbon) is added. 24 until the mixture absorbs no more hydrogen.
Keep at 60°C for an hour.
溶液をr過後、DMFを減圧下に50℃で蒸発する。コ
ポリマーをメタノール10cm″に溶解し、ジエチルエ
ーテル約100cm3で沈澱させる。ペースト状の形で
得られたポリマーを、オーブン中で真空下50℃で一夜
乾燥する。茶かっ色のコポリマー[式(rV)14 、
12gを酸として得る(収率84%)。After passing the solution through r, the DMF is evaporated under reduced pressure at 50°C. The copolymer is dissolved in 10 cm'' of methanol and precipitated with about 100 cm of diethyl ether. The polymer obtained in pasty form is dried in an oven under vacuum at 50° C. overnight. A brown-brown copolymer [formula (rV) 14,
12 g are obtained as acid (yield 84%).
実施例2の重合体の場合、反応時間を24時間経過して
も水素化分解が完全に達成されない。約6〜lO%のベ
ンジルエステル基かりシンに結合して残存する(プロト
ンNMRで測定)。それらは、反応混合物へ新たなパラ
ジウム化炭素0.5gを加えて水素化分解を繰り返すか
、あるいはDMF/4NIC+混合液(60/40、V
/V)中で環境温度で2時間加水分解することによって
除去できる。反応終末時、4NNaOI−1水溶液を加
えて溶液を中和してカット・オフ・ポイント6000〜
8000を備えた透析管[バイスキング(V iski
ng)社(米国)販売、カタログ番号24012]で水
に対して透析する。有機溶媒、塩およびオリゴマーを除
去した滞留物を凍結乾燥することにより式(■)の化合
物のナトリウム塩を水溶性の茶かっ色粉末の形で得る。In the case of the polymer of Example 2, hydrogenolysis was not completely achieved even after 24 hours of reaction time. Approximately 6 to 10% of the benzyl ester group remains bound to Karishin (measured by proton NMR). They either repeat the hydrogenolysis by adding 0.5 g of fresh palladized carbon to the reaction mixture, or the DMF/4NIC+ mixture (60/40, V
/V) at ambient temperature for 2 hours. At the end of the reaction, add 4N NaOI-1 aqueous solution to neutralize the solution until the cut-off point reaches 6000 ~
Dialysis tube equipped with 8000 [Viski
ng) (USA), catalog number 24012] against water. The sodium salt of the compound of formula (■) is obtained in the form of a water-soluble brown-brown powder by lyophilizing the retentate from which the organic solvent, salts and oligomers have been removed.
この塩のIRスペクトル(KBrディスク法)で、イミ
ドカルボニル基(1780cm−’および1790cm
−’)、アミドカルボニル基(1000cm−’および
1550cm−’)、カルボン酸塩(1600c1つの
特徴的な振動に対応する・5個のピークが1800〜I
500cm−’の間で認められる。The IR spectrum (KBr disk method) of this salt shows imidocarbonyl groups (1780 cm-' and 1790 cm-'
-'), amide carbonyl group (1000 cm-' and 1550 cm-'), carboxylic acid salt (1600c corresponding to one characteristic vibration, five peaks 1800 to I
It is recognized between 500 cm-'.
D jOを使用した”C−NMrえスペクトル(外部基
準:ビリジン)では、1つはイミド環に含まれた炭素に
対応する7 3 、1 ppmのピーク、もう1つは遊
離OHおよびCOOHが結合している炭素に対する75
.2ppI11のピークからなるクエン酸単位の4級炭
素に対する2重ピークが認められろ。イミド基の割合は
2つのピークの比表面積から計算して約90%である。In the "C-NMR spectrum using DjO (external reference: pyridine), one peak is at 73, 1 ppm corresponding to the carbon contained in the imide ring, and the other is the peak of free OH and COOH bonded. 75 for carbon
.. A double peak for the quaternary carbon of the citric acid unit consisting of a peak of 2ppI11 is observed. The proportion of imide groups is about 90% calculated from the specific surface areas of the two peaks.
このコポリマーの遊離酸の形は、その塩をデュオライト
(D uol ite、商標)C20MBのような■]
“型の陽イオン交換樹脂を通すことによって生成され、
凍結乾燥によって単離される。本島は無色の固体で、水
、芳香族溶媒および塩素化溶媒、テトラヒドロフラン、
ジオキサンに不溶であるが、メタノール、ジメチルホル
ムアミドおよびジメチルスルホキシドに溶解する。The free acid form of this copolymer can be combined with its salts such as Duolite™ C20MB.
“Produced by passing through a type of cation exchange resin,
Isolated by lyophilization. The main substance is a colorless solid that can be used in water, aromatic and chlorinated solvents, tetrahydrofuran,
Insoluble in dioxane, but soluble in methanol, dimethylformamide and dimethyl sulfoxide.
粗製重合体の接触水素化をDMFの代わりにジオキサン
/エタノール混合液(50150、■/V)中で実施す
るとベンジルエステル基の開裂は完全に達成されるが、
このようにして遊離したカルボン酸基の若干はエチルエ
ステルへと変換されろ。When the catalytic hydrogenation of the crude polymer is carried out in a dioxane/ethanol mixture (50150, ■/V) instead of DMF, complete cleavage of the benzyl ester groups is achieved;
Some of the carboxylic acid groups thus liberated will be converted into ethyl esters.
実施例4
塩基性媒質中の加水分解による式(V)のコポリマーの
製造
実施例3で得られた生成物4gを撹拌しながら0.7N
NaOH水溶液水溶液180c溶’する。Example 4 Preparation of a copolymer of formula (V) by hydrolysis in a basic medium 4 g of the product obtained in Example 3 were mixed with 0.7N with stirring
Dissolve 180c of NaOH aqueous solution.
添加の際に、反応媒質は瞬時橙紅色に変化する。Upon addition, the reaction medium instantly turns orange-red.
反応の5分後には色は消える。混合物を45分間撹拌す
る。反応終末時、塩基性溶液を100m1当り2gとな
るように調節して、透析管[ライスケース型(Wisk
ase+米国)、カット・オフ・ポイント6000〜8
000]中でl)Hが中性となるまで蒸留水に対して透
析する(約2日間)。ついで減圧上蒸発により滞留物を
50cffi3まで濃縮し、0.45μmミリボアメン
プランで濾過して、これを凍結乾燥する。式(V)のコ
ポリマーのナトリウム塩3゜tgが茶かっ色粉末形態で
得られる。水晶は水に可溶であるが、殆どの有機溶媒に
不溶である。平均分子ff135000(ゲル浸透クロ
マトグラフィーで測定。溶媒:0.I 5M KBr水
溶液、ポリスチレンスルホン酸塩:標準品)。The color disappears after 5 minutes of reaction. Stir the mixture for 45 minutes. At the end of the reaction, the basic solution was adjusted to 2 g per 100 ml, and a dialysis tube [rice case type (Wisk
ase+US), cut-off point 6000-8
[000] l) Dialyze against distilled water until H becomes neutral (approximately 2 days). The retentate is then concentrated to 50 cffi3 by evaporation under reduced pressure, filtered through a 0.45 μm millibore membrane run, and lyophilized. 3°tg of the sodium salt of the copolymer of formula (V) are obtained in the form of a brownish-brown powder. Quartz is soluble in water but insoluble in most organic solvents. Average molecular weight ff 135000 (measured by gel permeation chromatography. Solvent: 0.I 5M KBr aqueous solution, polystyrene sulfonate: standard).
コポリマー(V)の酸の形は、その塩の水溶液を[■“
型のデュオライト(商lfi)C20MB樹脂を通し、
その溶出液を凍結乾燥することによって得られる。The acid form of copolymer (V) can be prepared by preparing an aqueous solution of its salt [■“
Through the type of Duolite (commercial lfi) C20MB resin,
It is obtained by lyophilizing the eluate.
コポリマーは無色の粉末形で得られ、すべてのptrで
水に可溶であり、ジメチルホルムアミド、ジメチルスル
ホキシドおよびメタノールに溶解するが、塩素化溶媒、
テトラヒドロフラン、ジオキサン、アセトンには不溶で
ある。The copolymer is obtained in colorless powder form and is soluble in water at all ptrs, soluble in dimethylformamide, dimethyl sulfoxide and methanol, but in chlorinated solvents,
Insoluble in tetrahydrofuran, dioxane, and acetone.
IMNaOHによるカルボン酸基の滴定によって、繰り
返しの1単位当り2個のカルボン酸基の存在が確認され
た(1単位の大きさは315)。Titration of the carboxylic acid groups with IMNaOH confirmed the presence of two carboxylic acid groups per repeating unit (unit size 315).
IRスペクトル(KBrディスク法)で、カルボン酸基
(1740cm−’)およびアミド基(1650および
1550c11)の特徴的な3個のピークが+ 80
(1−1500cI++−’の間に認められた。In the IR spectrum (KBr disc method), three characteristic peaks of carboxylic acid groups (1740 cm-') and amide groups (1650 and 1550c11) are found at +80
(Recognized between 1-1500cI++-'.
実施例5
シスタミンHEN (C)L)* S S (
CHt)NII、およびシトロクロラールジクロリドか
ら出発するポリマーの製造
実験室用混合装置中で、塩酸シスタミン2.14g(9
,5,10−3モル)、炭酸ナトリウム・!0Hz0
5.44g(中和のため)およびドデシル硫酸ナトリウ
ム0.4gを激しく撹拌しながらベンゼン/水混合液(
60/40、V/V)50c+n3に溶解する。ベンゼ
ン30cm−’に溶解したシトロクロラールジクロリド
3.74g(10,4,I O−’モル)および水20
c+s−’に溶解した炭酸ナトリウム5.97g(20
,8,10−’モル)を、4分間で溶液の90%が添加
されるような速度でこれに加え、ついで1分間撹拌後、
残りの10%を1分間で追加する。ポリマーは反応媒質
から白味がかったペースト状の形で沈澱する。反応の終
末時、HCl水溶液を加えて酸性(pH2)とする。粗
製重合体を水洗し、真空下に50℃で乾燥する。ジオキ
ソランおよびイミド基を含存するポリマー3gが得られ
る。この生成物は強酸、N−メチルビC)リドン、ジメ
チルスルホキシドおよびツメデルポル12アミドに溶解
ずろが、水、アルコール類、塩素化溶媒には不溶である
。Example 5 Cystamine HEN (C)L)*SS (
CHt)NII, and citrochloral dichloride. In a laboratory mixing apparatus, 2.14 g cystamine hydrochloride (9
,5,10-3 mol), sodium carbonate! 0Hz0
5.44 g (for neutralization) and 0.4 g of sodium dodecyl sulfate were added to the benzene/water mixture (
60/40, V/V) Soluble in 50c+n3. 3.74 g (10,4,1 O-' mol) of citrochloral dichloride dissolved in 30 cm-' of benzene and 20 cm-' of water
5.97 g of sodium carbonate (20
, 8,10-' mol) was added to this at a rate such that 90% of the solution was added in 4 minutes, then after stirring for 1 minute,
Add the remaining 10% in 1 minute. The polymer precipitates from the reaction medium in the form of a whitish paste. At the end of the reaction, an aqueous HCl solution is added to make it acidic (pH 2). The crude polymer is washed with water and dried under vacuum at 50°C. 3 g of polymer containing dioxolane and imide groups are obtained. The product is soluble in strong acids, N-methylbiC)lidone, dimethyl sulfoxide, and thumedelpol-12amide, but insoluble in water, alcohols, and chlorinated solvents.
その赤外線スペクトルは実施例2−cの化合物と類似し
ており、!790および! 710cm−’に環式イミ
ド基の特徴的なピークおよび1650および1550c
m”にアミド基のピークを示す。Its infrared spectrum is similar to the compound of Example 2-c, and! 790 and! The characteristic peak of the cyclic imide group at 710 cm-' and 1650 and 1550c
The peak of the amide group is shown at m''.
0.7N Na0II水溶液で処理することによってイ
ミド環が開環し、得られた式(V)のポリマーはpH7
で水に可溶となる。The imide ring was opened by treatment with a 0.7N Na0II aqueous solution, and the resulting polymer of formula (V) had a pH of 7.
becomes soluble in water.
実施例6
し−シスチン II、N−C11−CHt、−3−3−
ell、−ell−Nll。Example 6 Cystine II, N-C11-CHt, -3-3-
ell, -ell-Nll.
C00II C00I+
およびシトロクロラールツクロリドから出発セろポリマ
ーの製造
(a) L−シスチンのジカルボン酸基の封鎖:I、シ
スデンジヘンシルエステルのノトンレートし一シスヂン
IOgのベンノルアルコール43ml溶液ftp−トル
エンスルホン酸17.4gのベンゼン100n+1溶液
に溶解する。すべての反応水が除去されるまで反応混合
物をディーンスターク式抽出器中で溶媒の還流温度で加
熱する。混合物を冷却し、メタノール50m1を加え、
ついでエチルエーテル500111を追加する。沈ja
28.8gが単離する。M、P、169〜171’c。Preparation of cellulose polymer starting from C00II C00I+ and citrochloral dichloride (a) Blocking of dicarboxylic acid group of L-cystine: I, notonlate of cysdine dihensyl ester and solution of monocysdine IOg in benol alcohol 43 ml ftp-toluenesulfone Dissolve 17.4 g of acid in a solution of 100n+1 benzene. The reaction mixture is heated in a Dean-Stark extractor at the reflux temperature of the solvent until all the water of reaction has been removed. Cool the mixture, add 50 ml of methanol,
Ethyl ether 500111 is then added. Shenja
28.8 g are isolated. M, P, 169-171'c.
(b)前記実施例と同様にして、L−シスチンジベンゼ
ンエステルのジトシレート10.34g、NFhCOz
” 10HtO7,74gおよびドデシル硫酸ナトリウ
ム0.7gのCs Hs/ H* 0混合液(66/3
3、V/V)78cm″溶液、ベンゼン52cm’に溶
解したシトロクロラールジクロリド5.57gの溶液お
よびNatCOs” l 0Ht0 8.9gの水2G
c+s’溶液で重縮合を実施する。(b) In the same manner as in the above example, 10.34 g of ditosylate of L-cystine dibenzene ester, NFhCOz
” Cs Hs/H*0 mixture (66/3
3. V/V) 78 cm'' solution, a solution of 5.57 g of citrochloral dichloride dissolved in 52 cm' of benzene and NatCOs'' l 0Ht0 8.9 g of water 2G
Polycondensation is carried out in c+s' solution.
反応混合物を処理した後、粗製ポリマー4.7gを白味
がかった固体として得る。本島は塩素化溶媒(CI−I
Cl3、Cl−1tel、)、ジオキサン、テトラヒド
ロフランおよびアセトンに可溶性で、アルコール、水、
エチルエーテルに不溶である。After working up the reaction mixture, 4.7 g of crude polymer are obtained as a whitish solid. The main island is chlorinated solvent (CI-I)
Cl3, Cl-1tel, ), dioxane, tetrahydrofuran and acetone, alcohol, water,
Insoluble in ethyl ether.
ポリマーを33%HBrの酢酸溶液で処理することによ
り、ベンジルエステル基の加水分解が行われる。Hydrolysis of the benzyl ester groups is achieved by treating the polymer with a 33% HBr solution in acetic acid.
Claims (15)
カルボキシル基を介し、クエン酸とジアミン類の縮合に
よって形成されたポリアミド類。(1) Polyamides formed by condensation of citric acid and diamines via carboxyl groups bonded to the 1- and 3-position carbon atoms of citric acid.
OHまたは−COOHによって置換されまたは置換され
ず、中間に酸素および硫黄原子(複数もあり得る)を挿
入してもよい直鎖式および分枝鎖式C_2〜C_1_0
脂肪族鎖から選ばれ、またはZはアリール鎖またはアル
キルアリール鎖から選ばれ〜はZが非対称である場合の
結合の2つの型を表す) で示される請求項1記載のポリアミド類。(2) Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, n is an integer lower than 1000, Z is a hydrophilic group -
Straight-chain and branched C_2 to C_1_0 which may be substituted or unsubstituted by OH or -COOH and may have intermediate oxygen and sulfur atoms(s) inserted
2. Polyamides according to claim 1, wherein Z is selected from aliphatic chains or Z is selected from aryl chains or alkylaryl chains and ~ represents the two types of bonding when Z is asymmetric.
のポリアミド類。(3) The polyamide according to claim 2, wherein Z is a C_2 to C_8 aliphatic chain.
1〜C_4アルキルから選ばれ、〜は非対称ジアミンに
よる結合の2つの型を表す) で示されるポリアミド類。(4) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R is C_6H_5, CCl_3, H or C_
Polyamides selected from 1 to C_4 alkyl, where ~ represents two types of bonding by asymmetric diamines.
、〜は非対称ジアミンによる結合の2つの型を表す) で示されるポリアミド類。(5) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, Z has the same meaning as described in claim 2, a and b are integers, ~ represents two types of bonding by asymmetric diamine) Polyamides.
2つの型を表す) からなるポリアミド類。(6) Formula Ap-Bq (where A is ▲ has a mathematical formula, chemical formula, table, etc. ▼ B is ▲ has a ▲ mathematical formula, chemical formula, table, etc. ▼ p and q are integers, ~ is the 2 of the bond due to the asymmetrical diamine polyamides consisting of two types).
結合しているCOOH基およびOH基は保護されている
)との重縮合を実施し、ついでその保護基をとり除くこ
とからなる請求項1記載のポリアミド類の製造方法。(7) A claim consisting of carrying out polycondensation of a diamine with citric acid (wherein the COOH and OH groups bonded to the carbon atom in position 2 are protected) and then removing the protecting group. Item 1. A method for producing polyamides according to item 1.
3または−C_6H_5から選ばれる) で示される保護されたクエン酸を使用する請求項7記載
の方法。(8) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R is H, C_1 to C_4 alkyl, -CCl_
8. The method according to claim 7, wherein a protected citric acid of the following formula is used.
る請求項7または8記載の方法。(9) The method according to claim 7 or 8, which comprises removing the protecting group by catalytic hydrogenation.
基をとり除くことからなる請求項7−9のいずれか1項
記載の方法。(10) A method according to any one of claims 7 to 9, which comprises removing the protecting group by reaction in a basic or acidic aqueous medium.
ド類[ここで、ZはOH基またはCOOH基(これらの
基は重縮合の前に保護されている)を含む]の製造方法
。(11) A method for producing a polyamide according to any one of claims 7 to 10 [wherein Z contains an OH group or a COOH group (these groups are protected before polycondensation)].
いる請求項11記載の方法。(12) The method according to claim 11, wherein COOH is protected in the form of a benzyl ester.
−6のいずれか1項記載のポリアミド類の用途。(13) Claim 1 of preparing a controlled release form of the pharmaceutical composition.
Use of the polyamide according to any one of -6.
は結紮糸を調製する請求項1−6のいずれか1項記載の
ポリアミド類の用途。(14) Use of the polyamides according to any one of claims 1 to 6 for preparing biodegradable surgical prostheses, sutures, or ligatures.
ずれか1項記載のポリアミド類の用途。(15) Use of the polyamide according to any one of claims 1 to 6 for preparing a biodegradable adhesive.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR8802956A FR2628432B1 (en) | 1988-03-08 | 1988-03-08 | CITRIC ACID POLYMERS AND DIAMINES, PROCESS FOR THEIR PREPARATION AND THEIR APPLICATIONS IN PARTICULAR AS MEDICAMENT VECTORS |
FR8802956 | 1988-03-08 |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH0222327A true JPH0222327A (en) | 1990-01-25 |
Family
ID=9364033
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP1054831A Pending JPH0222327A (en) | 1988-03-08 | 1989-03-07 | Polymer consisting citric acid and diamine, and its production and use |
Country Status (4)
Country | Link |
---|---|
US (1) | US5026821A (en) |
EP (1) | EP0332530A1 (en) |
JP (1) | JPH0222327A (en) |
FR (1) | FR2628432B1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2011503331A (en) * | 2007-11-15 | 2011-01-27 | ザ ユニバーシティー オブ モンタナ | Hydroxy polyamide gel former |
Families Citing this family (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2707878A1 (en) * | 1993-07-21 | 1995-01-27 | Imedex | New adhesive compositions for surgical use. |
FR2707992B1 (en) * | 1993-07-21 | 1995-10-13 | Flamel Tech Sa | New organic products containing reactive thiol functions, one of their preparation processes and the biomaterials containing them. |
US5480963A (en) * | 1994-07-22 | 1996-01-02 | United States Surgical Corporation | Absorbable copolymers derived from tricarboxylic acids and surgical articles made therefrom |
US20020183418A1 (en) * | 2001-02-02 | 2002-12-05 | Oren Rosen | Design and synthesis of instant-degradable plastics |
EP1501352B1 (en) | 2001-12-14 | 2015-02-18 | The University Of Wyoming | Controlled release of oxycodone |
US8293890B2 (en) | 2004-04-30 | 2012-10-23 | Advanced Cardiovascular Systems, Inc. | Hyaluronic acid based copolymers |
ITMO20050139A1 (en) * | 2005-06-03 | 2006-12-04 | Tartarica Treviso S R L | BIODEGRADABLE PLASTIC MATERIALS. |
JP4802250B2 (en) * | 2006-03-01 | 2011-10-26 | ザ プロクター アンド ギャンブル カンパニー | Fiber formed from ester condensate and method of forming fiber from ester condensate |
US20080200591A1 (en) * | 2007-02-15 | 2008-08-21 | Isao Noda | Melt Processable Reactive Pellets Capable of Forming Ester Condensates and Process for Forming Melt Processable Reactive Pellets |
FR2918888B1 (en) * | 2007-07-18 | 2009-10-23 | Centre Nat Rech Scient | CONTROLLED DELIVERY SYSTEM OF ACTIVE INGREDIENT AND PREPARATION METHOD |
US20090068416A1 (en) * | 2007-09-12 | 2009-03-12 | Isao Noda | Process for Coating a Substrate with a Coating Precursor Forming a Coating as a Product of Ester Condensation and Products Coated with Such Coating Precursor |
KR20140074388A (en) * | 2011-10-10 | 2014-06-17 | 테바 파마슈티컬 인더스트리즈 리미티드 | Rasagiline citramide |
US20140275467A1 (en) | 2013-03-15 | 2014-09-18 | Ethicon, Inc. | Polylactone Polymers Prepared from Monol and Diol Polymerization Initiators Processing Two or More Carboxylic Acid Groups |
CN108026266A (en) * | 2015-09-16 | 2018-05-11 | 巴斯夫欧洲公司 | New bio base amine |
BR112018013349B1 (en) | 2017-03-21 | 2023-10-24 | Cj Cheiljedang Corporation | ADHESIVE COMPOSITION AND METHOD OF PREPARING AN ADHESIVE COMPOSITION |
JP7362672B2 (en) | 2018-06-06 | 2023-10-17 | ビーエーエスエフ ソシエタス・ヨーロピア | Alkoxylated polyamidoamines as dispersants |
KR102284844B1 (en) | 2018-08-31 | 2021-08-03 | 씨제이제일제당 주식회사 | Method for suppressing an occurrence of dust, soil stabilizing composition, and spray device comprising soil stabilizing composition |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US1016833A (en) * | 1908-05-07 | 1912-02-06 | Otis Elevator Co | Electric-switch-contact holder. |
US4064086A (en) * | 1976-07-13 | 1977-12-20 | National Patent Development Corporation | Thermoplastic hydrogels |
US4873311A (en) * | 1988-02-05 | 1989-10-10 | Union Camp Corporation | Water dispersible polyamide ester |
-
1988
- 1988-03-08 FR FR8802956A patent/FR2628432B1/en not_active Expired - Fee Related
-
1989
- 1989-03-02 US US07/318,032 patent/US5026821A/en not_active Expired - Fee Related
- 1989-03-07 JP JP1054831A patent/JPH0222327A/en active Pending
- 1989-03-07 EP EP89400635A patent/EP0332530A1/en not_active Withdrawn
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2011503331A (en) * | 2007-11-15 | 2011-01-27 | ザ ユニバーシティー オブ モンタナ | Hydroxy polyamide gel former |
Also Published As
Publication number | Publication date |
---|---|
US5026821A (en) | 1991-06-25 |
FR2628432A1 (en) | 1989-09-15 |
EP0332530A1 (en) | 1989-09-13 |
FR2628432B1 (en) | 1990-12-21 |
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